First clinical experience with posterior lumbar interbody fusion using a thermal-sprayed silver-containing hydroxyapatite-coated cage

In this study, we observed 48 participants who underwent TLIF or PLIF using Ag-HA-coated interbody cages and collected information regarding the appropriateness of cage use. Of the 48 participants (51 intervertebral levels), only one experienced SSI, and no Ag-induced complications occurred. In addition, > 80% of participants showed clinically meaningful symptomatic improvement at 12 months postoperatively, and the fusion rate was 91%, which is clinically acceptable. The results of this study could provide valuable information for conducting subsequent clinical trials comparing Ag-HA cages with conventional cages.

To the best of our knowledge, this is the first trial to evaluate the safety and efficacy of the Ag-HA cage for lumbar interbody fusion in patients with lumbar spine disease. Although Ag has antibacterial activity, it is also associated with adverse effects such as cytotoxicity or poor cytocompatibility [22]. The antibacterial mechanism of action of Ag particles includes binding to the thiol groups of enzymes, cell membranes, and nucleic acids, which results in structural abnormalities, damage to cell membranes, and inhibition of cell division [23,24,25]. These multifunctional actions of Ag on different intercellular targets make it difficult for bacterial strains to develop resistance. Ag-coated megaprostheses have been used in clinical practice; however, high concentrations of Ag were demonstrated to be toxic to osteoblasts, inhibiting ossification and contributing to osteolysis and postoperative loosening of the prosthesis [26]. Because the cytotoxic effect of Ag appears to be dose-dependent, it is important to control the concentration of compounding materials to achieve optimal antibacterial and osteogenic properties simultaneously [22, 27]. Low concentrations of Ag were found to have no cytotoxic effects on osteoblasts in vitro [22, 27]. We developed Ag-HA by combining 3% Ag with HA, which is known to have high osteoconductivity, and demonstrated that 3% Ag-HA is a safe material [14, 16] with good osteoconductivity [8, 28] and antibacterial activity [13, 29, 30] that can be used in vitro, in vivo, and in humans. Moreover, previous studies have demonstrated that the use of 3% Ag-HA-coated implants in THA markedly improved activities of daily living without causing any adverse reactions attributable to Ag in the human body [15, 17]. After favorable in vitro and in vivo results were obtained, we conducted this clinical trial using Ag-HA cages in PLIF or TLIF. Most reports on antimicrobial implants in orthopedic surgery have involved limb fractures and bone tumor reconstructions, and there have been few reports of antimicrobial implants used in the spine [7].

Safety of the Ag-HA cage

Ag-related adverse reactions, such as argyria and mental or neurological disorders [31], hepatic and renal dysfunction [32], cytotoxicity [33], and mutagenicity [34], can result from a total dose of 4 g of Ag or a blood Ag concentration of ≥ 300 ppb [23, 32]. Regarding neurological damage, Seçinti et al. reported that the implantation of 23 g of Ag does not cause neuropathy, based on the listed dental literature [35]. The maximum amount of Ag contained in the Ag-HA implant for THA and the double cage was reported to be 3 mg [15] and 1.6 mg, respectively. In addition, after the insertion of the Ag-HA implant for THA, the blood Ag level was found to remain within the normal range (< 15 ng/mL), and the highest blood Ag level was 6.0 ng/mL [15]. Thus, in patients treated with the Ag-HA cage, the probability of developing argyria or other adverse reactions is considered extremely low, as shown in the present study. This is because the amount of Ag in the Ag-HA cage is much lower than that in the Ag-HA implant for THA, which has not been associated with any adverse events. In this study, no participant showed any signs of systemic and/or local argyria or neurological symptoms during the follow-up period. Thereafter, no patients showed any sign of wound dehiscence, systemic and/or local argyria, or neurological symptoms that worsened during the follow-up period. Implant failure did not occur in any of the patients.

In this study, a 58-year-old man with no underlying disease developed a deep infection. In the case of deep SSI in instrumented spine surgery, biofilm formation on the instrument is a major factor in the severity and refractoriness of the infection. In such cases, the removal of the instrument is frequently required. Although infection of the cage was considered in this case, the cage was not removed at the first revision surgery because of the expected effect of Ag-HA in inhibiting biofilm formation [36]. It may have been fortunate that the infection was cured with only the first reoperation, or it may have been due to the significant effect of Ag-HA. These possibilities would need to be confirmed in future large-scale studies.

Efficacy of the Ag-HA cage

The efficacy of the Ag-HA cage was evaluated based on clinical and radiological assessments. With regard to clinical findings that are effectiveness indicators, all patients showed an improvement in the NRS score for LBP and lower limb pain and the ODI score for LBP-related quality of life. In a systematic review of the quantitative evaluation of bony fusion in lumbar interbody fusion, Formica et al. [3] analyzed 67 articles, of which 31, 19, and 17 articles used X-ray, computed tomography (CT), and both. The review recommended that CT is the most effective method for assessing instability, whereas lateral dynamic X-rays alone are limited because they tend to produce false-negative results and a high rate of bone fusion. This study evaluated segmental instability and radiolucency or a gap around the implant using lateral dynamic X-rays and MDCT 12 months postoperatively. Previous reports that described the fusion rate in PLIF or TLIF were used to assess patients using lateral dynamic X-rays and MDCT, and the fusion rate ranged from 65 to 100% [3]. One of the main reasons for this wide variation in interbody fusion rate could be the insufficient common criteria for assessing arthrodesis [3, 16, 37]. In a systematic review by Formica et al., the mean bone fusion rates for PLIF (26 papers, 1591 patients) and TLIF (21 papers, 1819 patients) were 93% (95% CI 90–95; χ2: 64.4, degree of freedom (df): 25, p < 0.001; I2: 61.2%; τ2: 0.03) and 94% (95% CI 91–97; χ2 = 99.2, df: 20, p < 0.001; I2: 79.8%; τ2: 0.06) [3]. The fusion rate in patients in whom the Ag-HA cage was used in this study was 91% for all intervertebral spaces at 12 months after surgery; this rate appears acceptable. The fusion rate in patients in whom the Ag-HA cage was used in this study was 91% for all intervertebral spaces at 12 months after surgery; this rate seems acceptable. In PLIF and TLIF, in addition to intervertebral bone fusion, biological fixation of the bone and cage are very important. Intramedullary Ag-HA implants placed in the lower extremities reportedly showed good bone formation and osseointegration in rats and humans [15, 17, 30], although these have not been examined in the lumbar intervertebral space, which has poorer bone fusion conditions than those in the lower extremity marrow because of the difference in blood flow and the contact area between the bone and implant [38].

Recently, it has been reported that VECF after lumbar interbody fusion using a cage in the early postoperative period may be a predictor of pseudoarthrosis or non-fusion [39], and the relationship between VECF and non-fusion has been investigated for different types of interbody cages, including polyetheretherketone (PEEK), titanium, titanium-coated PEEK, and porous tantalum; however, no studies have investigated this relationship in patients treated using Ag-HA cages [39, 40]. In the present study, cage subsidence occurred in three cases (5.9%) at 12 months after surgery. The modulus of elasticity of the Ag-HA cage, which is made of titanium coated with Ag-HA, is the same as that of titanium and higher than that of bone. Although it has been hypothesized that a high modulus of elasticity leads to increased rates of subsidence [41], this was only observed in three cases in our study population. Cage subsidence may be prevented by adequate bone grafting and careful procedures that do not destroy the bony endplate. Regarding the suitability of VECF as an indicator of bone fusion, at 12 months postoperatively, we noted VECF incidences of 13.7% to 60% in the PEEK cage group, 0–17.3% in the titanium cage group, and 21.6% in the Ag-HA cage group. Thus, the PEEK cage tends to be associated with a higher incidence of VECF [39, 40], which seems true for the Ag-HA and titanium cages. The respective rates of VECF and bone fusion were 29% and 88% at 6 months after surgery and 22% and 91% at 12 months after surgery, respectively. Therefore, we speculated that the Ag-HA cage did not interfere with bone fusion and that VECF disappeared due to bone remodeling caused by reduced micromovement in cases where the bone fusion between the Ag-HA cage and the endplate progressed [42].

Limitations

The present study was associated with some limitations. First, the lack of a control group made it impossible to evaluate the superiority of AG-HA cages over conventional cages in terms of antimicrobial resistance and fusion rate. This research question should be addressed in subsequent clinical trials based on the results of this study. In addition, the safety of the Ag-HA cage may not have been adequately confirmed because of the small sample size and short follow-up period. This study population needs to be closely monitored, and further cases need to be accumulated. Therefore, a prospective multicenter clinical trial (UMIN 000039964) is currently underway.

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